The present invention is directed to a controlled release solid dosage form for biological components (BC). In addition, the invention is directed to a method of delivery of BCs over an extended timeframe.
As a biological substance passes through the gastrointestinal (GI) tract of humans or animals, it is subjected to a wide range of pH values ranging from the neutral pH of the mouth, to the acidic conditions of the stomach, and to the different conditions of the intestinal tract. The GI tract has significantly different conditions in the gastric portion, the stomach, as compared to the intestinal tract, the small and large intestines, due to different pH ranges. Because the majority of biologically active components are highly pH sensitive, these changes in pH can cause significant effects upon the stability of the BCs and their ability to function in vivo. For example, many proteins included in BCs denature in acidic environments. Once BC proteins are denatured, their biological activity, if still present, significantly differs from the non-denatured state. For a BC to be functional, it must survive the GI tract with minimal exposure to pH fluctuations. Further, BCs are also extremely sensitive to enzymes bringing about enzymatic degradation. For example, one barrier to the oral administration of insulin is its susceptibility to enzymatic degradation.
The oral administration of BCs without a controlled release delivery system has as a significant disadvantage not allowing the BC to bypass the low-pH and enzyme-rich environment of the stomach, thereby potentially decreasing the viability of the BC. For those devices which employ an enteric coating mechanism to survive the gastric environment, the shortcomings may be two-fold. First, the process of coating the dosage form or its contents with an enteric coating mechanism may result in significantly lowered viability of the BC. Second, the downfall of merely by-passing the stomach is the explosive delivery of the BC immediately upon exiting the stomach. This non-specific delivery is ineffectual and primitive in view of certain delivery needs of BCs because the bioavailability of BCs is often site dependent. Therefore, the enteric coating process typically used in the pharmaceutical industry is not used in this invention.
BCs may be targeted either through modification of the BC itself or through the controlled release of the BC within a desired physiologic window. One such BC that displays such site-specificity is the lactic acid bacteria, Lactobacillus Acidophilus, also referred to as a probiotic. Probiotic bacteria promote intestinal health by assisting the naturally occurring flora within the GI tract to reestablish themselves. Probiotics are also useful after antiobiotic therapy. L. Acidophilus is one example of other probiotics, including Lactobacillus bulgaricus, Lactobacillus casei subsp. Rhamnosus, Lactobacillus casei subsp. Casei, Lactobacillus salivarius, Lactobacillus brevis, Lactobacillus reuteri, Lactococcus lactis subsp. Lactis, Enterococcus faecium, Lactobacillus plantarum, Streptococcus thermophilus, Bifidobacterium infantis, Bifidobacterium Bifidum, Bifidobacterium longum, Saccharomyces boulardii, and various modified soil organisms.
Various strains of probiotic organisms will attach at a different locations of the intestinal tract, preferentially attaching within a region either slightly proximal or distal to other probiotic strains of the same, or nearly the same genus. These preferential regions of attachment are of particular importance relative to employing the probiotic as delivery systems for genomic or proteomic therapy, whether directly or as carriers for other vectors containing genetic or proteomic BCs.
Beneficial microorganisms, for example, but not limited to, gastrointestinal flora such as lactic acid bacteria and yeast are an essential constituent of metabolism and immune response. Supplementation of beneficial microorganisms is a valid mechanism for replacement of flora lost due to antibiotic treatment, enhancement of naturally-occurring levels of beneficial flora, enhancing competitive inhibition and otherwise preventing enteropathogens, and altering the metabolism of ingested substances. Probiotics are one example of beneficial microorganisms.
Solid oral dosage forms employing controlled release have been increasingly demonstrated to be beneficial to the administration of pharmaceutical compounds, enhancing safety and consumer compliance, minimizing side effects and providing new therapeutic benefits. The four generalized platforms for controlled release solid oral dosage forms are diffusion, reservoir, pore-forming wax, or coated-bead systems. These platforms for controlled release have generally not been applied to BCs, however, due to high development costs, bioavailability issues, and internal instability of the BC within the dosage form. Where these platforms have been applied to BCs, the applications have not resulted in controlled release of the BCs. In the past, enteric coating technologies and other mechanisms of delayed release have been limited to features with explosive delivery after the stomach rather than controlled release and delivery of the BCs.
Controlled release delivery systems can take many forms including polymeric matrix systems, wax matrix systems, multi-particulate systems, and combinations thereof. The most commonly used delivery systems can be broadly classified as diffusion, reservoir, pore-forming wax, or coated-bead systems. Diffusion devices are composed of a drug dispensed in a polymer which diffuses from the entire physical tablet. Reservoir devices usually consist of a semi-permeable barrier which is involved in the release of the active ingredient from a core site within the tablet. Coated-bead systems employ a pH-sensitive or enteric coating of aggregated particles of the active ingredient packaged in capsule form. Pore-forming wax systems incorporate the active ingredient into a wax base and rely upon the rate of diffusion to control the release of the active ingredient.
In tableted, pore forming wax matrices, the BC and a water-soluble polymer are introduced into a wax or wax-like compound such as paraffin or guar gum, and then placed in an aqueous environment so as to allow the water-soluble polymer to dissolve out of the wax, resulting in the formation of pores. Upon contact with the GI fluid, the pores facilitate diffusion-mediated release of the BC. The rate of release of the BC is dependent upon non-linear erosion.
Coated-bead systems are one of the few delivery systems available in both tablet and capsule forms. The BC is encased within a bead using one of the varieties of processes available, such as spheronization-extrusion or coating of non-pareils. The coated BC is then further coated with an enteric coating or employed in a blend of coated beads with differing release rates for extended release formulations. The BC may also be blended or granulated with polymers before enteric coating to provide an additional level of control. The coated beads themselves may also be combined with polymers to create a hybrid diffusion or wax-based system. Coated-bead systems are complex to manufacture, requiring large numbers of excipients, use of solvents, and long manufacturing time. The use of such solvents and the manufacturing processes required to apply such solvents may expose the BC to adverse environmental conditions and cause a loss of the viability of the BC. This is especially concerning in the case of lyophilized BCs, where any exposure to moisture may cause significant reduction in viability.
An example of a reservoir system is the push-pull osmotic pump. These osmotically-controlled delivery systems feature a bi-layer tablet coated with a semi-permeable membrane, possessing a laser-bored orifice through which the BC is pushed as aqueous solution is absorbed into the tablet. There are a number of osmotic delivery systems on the market that work via a similar physical principle; these osmotic systems produce very replicable, linear release. Manufacturing this osmotic delivery system is definitively non-conventional, requiring specialized equipment and additional processing steps. The inherent complexity of the design adds corresponding complexity to the development and scale-up of any osmotic membrane product.
The diffusion tablet systems rely on hydrophilic polymer swelling for control of BC release. These polymer systems can be sub-classified as conventional hydrogel systems and modified polymer systems. Conventional hydrogel systems rely upon the penetration of water to form a gel-like phase through which the bioactive agent is released. These hydrogel systems often incorporate the BC in a single polymer such as polyethylene oxide or hydroxypropyl methylcellulose. In the case of the modified polymer systems, polymers with differing physical characteristics—such as one that is hydrophilic (e.g. HPMC), and one that is pH-dependent in its swelling characteristics (e.g. pectin), are combined with the BC. When these polymers interact with dissolution media, a transition phase or interfacial front develops, forming a gradually dissociating semi-solid core surrounded by a gel periphery that allows the BC to be increasingly released as the matrix hydrates. The movement of the dosage form through the GI tract, through regions of increasing pH, permits further swelling and erosion of the matrix, culminating in a complete release of the BC and complete dissolution of the dosage form.
Prior art formulations cannot deliver beneficial microorganisms as part of BCs over an extended time period or to targeted individual regions of the GI tract. Prior art formulations require coating processes such as enteric coating to achieve gastric or stomach bypass. Further, prior art formulations fail to provide mechanisms for pH control thereby rendering pH sensitive strains much less viable due to variations in the pH of the GI tract. Further, prior art formulations lack mechanisms for isolating the BC from enzymatic degradation. Prior art formulations lack mechanisms to increase the stability of the dosage form itself through sequestration of available water. Prior art formulations utilizing dietary fiber as a carrier require too large a volume for efficient oral dosage form manufacture. These and other limitations and problems of the past are solved by the present invention.